DELAYED
RADIATION INJURIES (SOFT TISSUE AND BONY NECROSIS)
Introduction
Hyperbaric oxygen is among the most
studied and frequently reported applications in the treatment of delayed
radiation injuries. This application of hyperbaric oxygen to the treatment and
prevention of delayed radiation injury will be the topic of this chapter. The
management of delayed radiation injury, especially when bone necrosis is
present, requires mult-disciplinary management. The nature of delayed radiation
injury, the mechanisms whereby hyperbaric oxygen is effective, clinical
results, the effects of hyperbaric oxygen on cancer growth and future areas for
research will be discussed.
The
Nature Of Radiation Injury
Radiation injuries should be
further sub-classified as acute, sub-acute or delayed complications.(1) Acute injuries are due to direct and near immediate cellular toxicity caused by
free radical-mediated damage to cellular DNA. Many cells suffer a mitotic or
reproductive death, i.e. enough damage has been rendered to the DNA that
successful subsequent mitosis is prevented. Acute injuries are usually
self-limited, and are treated symptomatically. However, they can be very
debilitating during their duration. Sub-acute injuries are typically
identifiable in only a few organ systems, e.g. radiation pneumonitis following
the treatment of lung cancer with an onset typically 2 to 3 months after
completion of irradiation. Subacute injuries have been shown to occur in the
lung with a clinical syndrome mimicking bronchitis. They have also been shown
to occur in the spinal cord where temporary demyelinization causes the
so-called Lhermitte’s syndrome where patient’s experience electric-like shocks
down their legs with spinal extension.
These, too, are generally self-limited but occasionally evolve to become
delayed injuries. Some sub-acute injuries may persist for several months.
Delayed radiation complications are typically seen after a latent period of six
months or more and may develop many years after the radiation exposure.
Sometimes, acute injuries are so severe that they never resolve and evolve to
become chronic injuries indistinguishable from delayed radiation injuries.(2)
These are termed “consequential effects” and are not characterized by a
symptom-free latent period. Often, delayed injuries are precipitated by an
additional tissue insult such as surgery within the radiation field.
A role for hyperbaric oxygen in
acute and sub-acute radiation injuries has not been well-studied or
established, although there is some interest in pursuing this application.(3)
The
Etiology Of Delayed Radiation Injury
The exact causes and biochemical
processes leading to delayed radiation injury are complex and only partially
understood at this time. In virtually all organ systems which demonstrate
radiation damage, we observe vascular changes characterized by obliterative
endarteritis. Because hyperbaric oxygen has been shown to enhance angiogenesis
in hypoxic tissues, the hyperbaric oxygen community has previously postulated
that the enhancement of angiogenesis was the primary if not the sole
therapeutic effect of hyperbaric oxygen in radiated tissues. Some radiation
biologists are now convinced that in some organ systems vascular changes play at
most a minor role in the evolution of delayed radiation injury.(4)
A more complex model of radiation
damage continues to evolve in the radiation oncology community. In the past,
radiation oncologists had made a distinction between the causes of acute and
delayed injuries. The belief was that they were not directly related. Indeed,
it is not uncommon to find a patient with serious acute reactions who will not
suffer significant chronic complications or someone with severe chronic
complications who had experienced no worse than average acute reactions to the
radiation. Radiation scientists now appreciate that the process of radiation
injury begins at the time of radiation treatment and involves the elaboration
and release of many bioactive substances including very prominently
fibrogenetic cytokines.(5) A
primary mechanism whereby therapeutic radiation inflicts damage on normal
tissues has been termed the fibro-atrophic effect.(4) This model
emphasizes the consequences of the observed depletion of parenchymal and stem
cells and de-emphasizes the impact of vascular damage. It also highlights the
exuberant fibrosis usually found in severely damaged irradiated tissues.(4-6,8)
In this model vascular damage and stenosis continue to be recognized as a
consistent finding in tissues exhibiting radiation damage including frank
necrosis; however, endarteritis as a causative factor for delayed radiation
injuries is de-emphasized.
A recent review of the delayed
fibro-atrophic effects of radiation has been accomplished by Fleckenstein et
al.(5) This paper identifies TGF-beta as the most frequently studied
cytokine associated with radiation injury. Additional cytokines associated with radiation injury
include IL-1, IL-2, IL- 4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17,
TNF-alpha and GMCSF.
Many studies of cytokines and
radiation injuries have been accomplished in animal models of radiation-induced
pneumonitis.(9) At the present, we are not able to make practical
clinical application of these observed associations. No single marker is likely
to provide us with a reliable estimate of future radiation damage.(10) Similarly, no practical strategies have as yet
been developed to prevent or reduce the production of these cytokines or reduce
their impact in a prophylactic fashion. We know that there is a very wide range
of tolerance to radiation and that some patients are much more sensitive to
radiation injury. If reliable predictors of delayed radiation injury were
available, adjustments to the radiation dosing scheme could be made for the
radio-sensitive patient. Some patients might be advised to seek alternative
therapies instead of radiation. Moreover, prophylactic interventions such as
hyperbaric oxygen or other yet to be developed pharmacologic interventions could
be applied during the latent period but before the manifestation of the chronic
injury. The hope and expectation would be that, by identifying a group at risk
and intervening in this group before manifestation of the injury, delayed
radiation injury could be prevented or at least reduced in its severity.
Obviously this postulate will have to be subjected to clinical trials.
The
Effects Of Hyperbaric Oxygen On Irradiated Tissues
Because a consistent cause and
manifestation of radiation injury is vascular obliteration and stromal
fibrosis, the known impact of hyperbaric oxygen in stimulating angiogenesis is
an obvious and important mechanism whereby hyperbaric oxygen is effective in
radiation injury. HBO2 induces neovascularization in hypoxic
tissues. Marx(11) has demonstrated the enhanced vascularity and
cellularity in heavily irradiated tissues after hyperbaric oxygen therapy by
comparing histologic specimens from patients pre- and post- hyperbaric oxygen.
Marx6 has also demonstrated the serial improvement in transcutaneous
oxygen measurements of patients receiving hyperbaric oxygen as an indirect
measure of vascular improvement. Marx et al(12) in an animal model
have shown increased vascular density in rabbit mandibles after exposure to
hyperbaric oxygen.
Feldmeier and his colleagues(7,8)
in a murine model of radiation damage to the small bowel have shown that
prophylactic hyperbaric oxygen can reduce the degree and mechanical effects of
fibrosis by being applied prior to the manifestation of radiation injury.
Assays of the murine bowel for collagen content and compliance included a
mechanical stretch assay as well as quantitative histologic assays of fibrosis
in the tunica media of the animal bowel utilizing Mason’s trichrome staining.
This author has personally
observed significant reduction in the woody fibrosis of soft tissues seen
frequently in head and neck cancer patients after radiation with a course of
hyperbaric oxygen intended to treat mandibular necrosis. To my knowledge, this
effect has not yet been systematically studied.
The hyperbaric study group headed
up by Dr. Thom(13,14) at the University of Pennsylvania has recently
published two studies demonstrating that hyperbaric oxygen can mobilize stem
cells by increasing nitric oxygen. This mechanism has not as yet been proven to
have a major impact on irradiated tissues. However, a putative effect on
increasing stem cells at the site of radiation injury is confirmed to some
extent by Marx’s(6) demonstration of increased cellularity and
vascularity in patients who have received hyperbaric oxygen for mandibular
osteoradionecrosis.
The impact of hyperbaric oxygen
in terms of its beneficial effects is likely to involve all three of the above
mechanisms in irradiated tissues: 1) Hyperbaric oxygen stimulates angiogenesis
and secondarily improves tissue oxygenation; 2) Hyperbaric oxygen reduces
fibrosis; and 3) Hyperbaric oxygen is likely to mobilize and stimulate an
increase of stem cells within irradiated tissues. The third mechanism is at
this point putative and remains to be proven in radiation damaged tissues.
Hyperbaric oxygen has been
applied as a therapy for delayed radiation injury for more than 30 years.
Informal surveys have shown that at most hyperbaric centers in the U.S., nearly
one half of patients receiving hyperbaric oxygen are being treated for
radiation injury. Hyperbaric oxygen also has a frequent application in the
prevention of mandibular osteoradionecrosis when dental extractions are
required from heavily irradiated mandibles. The following sections will address
the application of hyperbaric oxygen to radiation complications on an anatomic
basis beginning with mandibular osteoradionecrosis.
Hyperbaric
Oxygen As Treatment For Mandibular Radiation Necrosis (ORN)
The
most widely applied and most extensively documented indication for hyperbaric
oxygen in chronic radiation injury is its application in the treatment and
prevention of radiation necrosis of the mandible. Multiple publications
describing the use of hyperbaric oxygen in the treatment of mandibular necrosis
have appeared in the medical literature since the 1970’s.
The likelihood of mandibular
necrosis as a result of therapeutic radiation varies widely among several
reports. Bedwinek(15) has reported a 0% incidence below doses of
6,000 cGy increasing to 1.8% at doses from 6,000 to 7,000 cGy and to 9% at
doses greater than 7,000 cGy. In his comprehensive review of radiation
tolerance, Emami(16) estimates a 5% incidence when a small portion
of the mandible (less than 1/3) is irradiated to 65 Gy or higher and a 5%
incidence at 60 Gy or higher when a larger volume of the mandible is
irradiated. It has been reported that 85% or more of cases resulting in exposed
mandibular bone will resolve spontaneously with conservative management.(17)
Unfortunately the remaining cases generally become chronic and may become
progressive, often further complicated by associated soft tissue necrosis.
Much of the early work in this
area considered radiation induced mandibular necrosis to be a subset of
mandibular osteomyelitis.(11) Also, hyperbaric oxygen was delivered
frequently as the sole treatment for mandibular necrosis without appropriate
surgical management after failure of more conservative therapy. Although many
cases would show temporary improvement, almost all cases of moderate to severe
ORN would recur if hyperbaric oxygen was administered without appropriate
surgical intervention.(18)
Dr. Robert Marx, D.D.S.(18,19)
elucidated many basic principles in the etiology and management of mandibular
ORN which have led to a rationale approach to its management. He has provided
several key principles in the understanding of the pathophysiology of
mandibular necrosis. He has demonstrated that infection is not the primary
etiology of mandibular necrosis by obtaining deep cultures of affected bone and
showing the absence of bacteria. We now understand that osteoradionecrosis is
the result of an avascular, aseptic necrosis. Marx(6) has also shown
that for hyperbaric oxygen to be consistently successful, it must be combined
with surgery in an optimal fashion. Marx
has developed a staging system for classifying mandibular necrosis. This staging system is applied to determine
the severity of mandibular necrosis. In addition it permits a plan of therapeutic
intervention, which is a logical outgrowth of the stage/severity of necrosis.
Stage I ORN: This stage includes those patients with
exposed bone who have none of the serious manifestations found in Stage III and
described below. Generally, before hyperbaric oxygen, these patients have had
chronically exposed bone or they have rapidly progressive ORN. These patients
begin treatment with 30 HBO2 sessions followed by only minor bony
debridement. If these patients’ response is adequate, an additional 10 daily
treatments are given, and the patients are followed to complete clinical
resolution.
Stage II ORN: If patients are not progressing appropriately
at 30 daily treatments or if a more major debridement is needed, they are
advanced to Stage II and they receive a more radical surgical debridement in
the operating room followed by 10 post-operative treatments. Surgery for Stage
II patients must maintain mandibular continuity. If mandibular resection is
required, patients are advanced to Stage III.
Stage III ORN: In addition to those failing treatment in
Stage I or II, patients who present initially with grave prognostic signs such
as pathologic fracture, orocutaneous fistulae or evidence of lytic involvement
extending to the inferior mandibular border are treated in Stage III from the
outset. When a patient is assessed to be at Stage III, mandibular segmental
resection is a planned part of the treatment. In Stage III, patients are
entered into a reconstructive protocol after mandibular resection. Marx has
established the principle that all necrotic bone must be surgically eradicated
here and in Stages I and II. Stage III
patients receive 30 daily hyperbaric treatments prior to mandibular resection
followed by 10 post-resection treatments. Typically after a period of several
weeks, the patients complete a reconstruction which may involve various
surgical techniques including free flaps or myocutaneous flaps. In its original
design, the reconstruction made use of freeze-dried cadaveric bone trays from a
split rib or iliac crest combined with autologous corticocancellous bone
grafting. In his original work at Wilford Hall USAF Medical Center, Marx had
reconstruction patients complete a full additional course of hyperbaric
treatments in support of the reconstruction. Marx has subsequently found that
the vascular improvements accomplished during the initial 40 hyperbaric
exposures are maintained over time and patients can undergo reconstruction
without a second full course of HBO2. Patients do receive 10 hyperbaric
treatments after the reconstructive surgery to support initial tissue metabolic
demands.
Marx(6) has reported his results in 268 patients treated
according to the above protocol. In his hands with this technique, successful
resolution has been achieved in 100% of patients. Unfortunately the majority of patients (68%)
required treatment as Stage III patients necessitating mandibular resection and
reconstruction. Dr. Marx requires that patients achieve reasonable cosmetic
restoration as well as the success in supporting a denture before he counts
them a success. These two issues, cosmesis and restoration of dentition for
mastication, are necessary components in improving quality of life in this
group of patients.
Feldmeier and Hampson(20) published a review of Hyperbaric
Oxygen in the treatment of radiation injury in 2002. A total of 14 papers
reporting the results in the treatment of mandibular necrosis were included.
All but one of these were case series. A single study by Tobey et al(21) was
a positive randomized controlled trial. It was a small study with only 12
patients enrolled; however, it was double blinded and reported to be a positive
trial by the authors. Details of randomization and outcome determinants were
not clearly stated. Patients received either 100% oxygen at 1.2 ATA or 2.0 ATA.
The paper states that those treated at 2.0 ATA “experienced significant
improvement” compared to the control group.
In this review, only one report of the remaining 13 publications, the
publication by Maier et al,(22) failed to report a positive outcome
in applying hyperbaric oxygen to the treatment of mandibular ORN. Maier and
colleagues added hyperbaric oxygen to their management only after the
definitive surgery was done. They failed to heed Marx’s guidance that the
optimal management of mandibular ORN requires that the majority of HBO2
be given prior to surgical debridement, resection or reconstruction in order to
improve the quality of tissues prior to surgical wounding.
Since the review by Feldmeier and Hampson(20) several
additional papers have been added to the literature. A multi-institutional randomized controlled
trial by Annane et al(23) reported negative results in their study
applying hyperbaric oxygen to Marx Stage I ORN.
These results have created a stir in the hyperbaric oxygen community,
and have prompted criticism of its methods from several sources. Patients were randomized to receive either 90
minutes of 100% O2 at 2.4 ATA or a breathing gas mix equivalent to
air at seal level for 30 daily treatments. The study design has received
criticism from several circles. The most serious flaw in the study design was
its failure to adhere to Marx’s guidance and to integrate hyperbaric oxygen
into a multi-disciplinary approach to ORN treatment. The study’s apparent
intent was to investigate whether the application of hyperbaric oxygen could
obviate the need for surgery in early mandibular ORN. It is not surprising that
the study had negative results because more than 2 decades earlier Marx had shown
an absolute necessity of surgically eradicating all necrotic bone. The need to
debride all necrotic bone to achieve resolution was also confirmed by Feldmeier
et al in their review of chest wall necrosis including some cases with ORN of
the ribs and sternum.(24)
Additional criticisms of this study by Annane(23) have been made. Moon et al(25)
have shown that nearly 2/3’s of the hyperbaric group received fewer than 22
hyperbaric treatment. Laden(26) points out that the patients
assigned to the control group had a risk for developing decompression sickness
with the gas mix they breathed (9% oxygen and 91% nitrogen) at 2.4 ATA. This
gas mix was designed to provide an inspired oxygen partial pressure equivalent
to air at seal level.
In another recent report, Gal and associates(27) have
published their results in treating a series of 30 patients with Marx Stage III
mandibular ORN with debridement and reconstruction employing microvascular
anastomosis. Twenty-one of these patients had previously been treated with
hyperbaric oxygen without resolution, although it is not clear that any of
these patients received a full course of treatment. At least some had had some
debridement prior to coming to Gal. Once in the author’s hands, they all had
appropriate debridement and reconstruction with free flaps. Those patients who
had not seen hyperbaric oxygen previously had a complication rate of 22% while
the group who had received at least some hyperbaric oxygen had a much higher
rate of complications of 52%. Of course this was not a randomized trial, and
even the authors suggest that the hyperbaric group may have represented a group
with refractory mandibular ORN. Obviously, those principles previously
established by Marx, i.e. an emphasis on pre-surgical hyperbaric oxygen,
debridement of all necrotic bone followed by reconstruction with post-operative
hyperbaric oxygen were not followed. The authors of this paper also discuss
that Marx Stage III ORN patients represent a heterogeneous group with a broad
range of injuries, severity of injuries, and a subsequent broad range of
outcomes.
Teng and Futran(28) have recently published their opinion
that hyperbaric oxygen has no role in treating ORN. Their article presents no
new clinical data and is a review article. The authors base their conclusions
on the Annane study and the advancement of the fibro-atrophic model of
radiation injury as now being dominant in the opinion of most experts of
radiation pathology. Mendenhall,(29)
a radiation oncologist from the University of Florida, in an editorial
accompanying the Annane paper in the Journal of Clinical Oncology points out
that the Annane paper was underpowered and therefore subject to question. He
goes on, however, to state his belief that hyperbaric oxygen is not indicated
for mandibular ORN although he remarks that it is hard to understand why the
HBO2 group in the Annane study did worse than control.
Suffice it to say that these recent papers addressing the efficacy of
hyperbaric oxygen in the treatment of ORN have expressed negative opinions.
Only one was a randomized controlled trial, and it is subject to the criticisms
in design discussed above. If we look at the total body of literature reporting
the impact of hyperbaric oxygen on mandibular ORN, we find the following: In the
publications reviewed in the Feldmeier/Hampson review,(20) 371 cases
of mandibular ORN are reported with a positive outcome in 310 or 83.6%.
Unfortunately, some of the papers report improvement rather than resolution as
their outcome determinate. Of course a better determination of outcome would be
resolution. In Marx’s(6) reports, resolution is reported in 100%.
Marx also indicates that success in Stage III patients requires not only
re-establishment of mandibular continuity but also rehabilitation with a
denture for cosmesis and mastication. By contrast if we look at the recent
“negative” trials, only 22 patients are included in the Gal report(30)
and 31 patients randomized to hyperbaric oxygen in the Annane(26)
trial for a total of 53 patients. Practitioners of hyperbaric oxygen who treat
mandibular ORN must do so in a multi-disciplinary manner and insure that
treatment includes an oral surgeon who can accomplish the needed extirpation of
necrotic bone.
______________________
More Information and References can be found
in the 12th Edition of the Hyperbaric Oxygen Therapy Indications
Book. For Sale on
the UHMS
Publications page.